Mitochondrial dysfunction resulting from nucleoside analogue reverse transcriptase inhibitor (NRTI) treatment may underlie many of the metabolic abnormalities seen in HIV-infected patients, including those of glucose metabolism. In this proposal we will test the hypothesis that supplementation with uridine, a pyrimidine nucleoside that abrogates NRTI-toxicity in vitro, can improve glucose metabolism in such patients. To date, use of this promising CAM therapy has been limited by issues of bioavailability. Recently, a dietary supplement with a high content of nucleosides (NucleomaxX(r)) has been shown to increase plasma uridine concentrations to levels thought to be sufficient to reverse mitochondrial dysfunction. In studies performed in the GCRC at San Francisco General Hospital we will: characterize single and multiple dose uridine pharmacokinetics (PK) in normal volunteers (Aim 1); perform a randomized double-blind placebo-controlled study in HIV-positive subjects who are currently on antiretroviral regimens containing stavudine or zidovudine and who have evidence of impaired mitochondrial function and insulin resistance (Aim 2). For Aim 2, 20 subjects will be hospitalized in the GCRC for 6 days to undergo comprehensive metabolic testing and a PK study. They will then be randomized, in a 1:1 fashion, to receive either NucleomaxX(r) or placebo for two months, after which they will repeat the 6-day GCRC-based assessments. Specifically, we will test the hypotheses that, in comparison to placebo, uridine supplementation will: improve hepatic and peripheral insulin sensitivity (hyperinsulinemic euglycemic clamp with stable isotope infusion) and glucose tolerance (frequently sampled intravenous glucose tolerance test); increase lipid disposal; improve mitochondrial function (31 P-magnetic resonance spectroscopy, plasma lactate levels, measures of oxidative stress and muscle mtDNA content) and decrease hepatic lipid levels (CT scan). We will also evaluate the effects of uridine supplementation on whole-body and regional fat and lean tissue distribution (dual-energy X-ray absorptiometry and abdominal CT). If uridine supplementation improves glucose metabolism with no deleterious effects in this small group of patients with NRTI-associated mitochondrial dysfunction, our findings would provide a basis for larger trials in patients with HIV infection as well as in seronegative type 2 diabetics or prediabetics and in patients with the polycystic ovary syndrome and fatty liver disease. [unreadable] [unreadable] [unreadable]